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Objective: To develop a fibromyalgia (FM) survey questionnaire for epidemiologic and clinical studies using a modification of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (ACR 2010). We also created a new FM symptom scale to further characterize FM severity., Methods: The ACR 2010 consists of 2 scales, the Widespread Pain Index (WPI) and the Symptom Severity (SS) scale. We modified these ACR 2010 criteria by eliminating the physician's estimate of the extent of somatic symptoms and substituting the sum of 3 specific self-reported symptoms. We also created a 0-31 FM Symptom scale (FS) by adding the WPI to the modified SS scale. We administered the questionnaire to 729 patients previously diagnosed with FM, 845 with osteoarthritis (OA) or with other noninflammatory rheumatic conditions, 439 with systemic lupus erythematosus (SLE), and 5210 with rheumatoid arthritis (RA)., Results: The modified ACR 2010 criteria were satisfied by 60% with a prior diagnosis of FM, 21.1% with RA, 16.8% with OA, and 36.7% with SLE. The criteria properly identified diagnostic groups based on FM severity variables. An FS score ≥ 13 best separated criteria+ and criteria- patients, classifying 93.0% correctly, with a sensitivity of 96.6% and a specificity of 91.8% in the study population., Conclusion: A modification to the ACR 2010 criteria will allow their use in epidemiologic and clinical studies without the requirement for an examiner. The criteria are simple to use and administer, but they are not to be used for self-diagnosis. The FS may have wide utility beyond the bounds of FM, including substitution for widespread pain in epidemiological studies.

Objective: To develop simple, practical criteria for clinical diagnosis of fibromyalgia that are suitable for use in primary and specialty care and that do not require a tender point examination, and to provide a severity scale for characteristic fibromyalgia symptoms., Methods: We performed a multicenter study of 829 previously diagnosed fibromyalgia patients and controls using physician physical and interview examinations, including a widespread pain index (WPI), a measure of the number of painful body regions. Random forest and recursive partitioning analyses were used to guide the development of a case definition of fibromyalgia, to develop criteria, and to construct a symptom severity (SS) scale., Results: Approximately 25% of fibromyalgia patients did not satisfy the American College of Rheumatology (ACR) 1990 classification criteria at the time of the study. The most important diagnostic variables were WPI and categorical scales for cognitive symptoms, unrefreshed sleep, fatigue, and number of somatic symptoms. The categorical scales were summed to create an SS scale. We combined the SS scale and the WPI to recommend a new case definition of fibromyalgia: (WPI > or =7 AND SS > or =5) OR (WPI 3-6 AND SS > or =9)., Conclusion: This simple clinical case definition of fibromyalgia correctly classifies 88.1% of cases classified by the ACR classification criteria, and does not require a physical or tender point examination. The SS scale enables assessment of fibromyalgia symptom severity in persons with current or previous fibromyalgia, and in those to whom the criteria have not been applied. It will be especially useful in the longitudinal evaluation of patients with marked symptom variability.

Address arthritis-associated pain as a disease entity, not as a sensory entity. Attempt to classify chronic pain as nociceptive pain, neuropathic pain, fibromyalgia-type pain, or psychogenic pain (very uncommon); specific treatment approaches are required for these different types of pain. Overcome your negative bias against fibromyalgia and review recent discoveries that have led to classification of fibromyalgia as a biologically-based neurosensory disorder. Use the simple and convenient ways that are available to measure pain and its concomitants (fatigue, poor sleep, depression, anxiety, and impaired physical functioning) both at initial evaluation and in follow-up visits as a guide to therapy. Do not fear use of opioids; just be careful with this class of drug.

Henry Kunkel spent nearly his entire professional life doing basic and clinical research at Rockefeller University. Many believe that he deserved to be a Nobel Laureate, not for one line of investigation, but for several in entirely distinct areas of medicine. Many of the leaders in immunology research during the last 50 years, especially research on systemic lupus erythematosus, received their research training in Henry Kunkel's laboratory. In this article, I attempt to illustrate his genius as a mentor from recollections of his scientific style and approach when I was a fellow in his laboratory almost 30 years ago. Henry Kunkel's legacy as a mentor continues today through the continuing contributions of his Fellows and their own trainees in immunological research.

Fibromyalgia and other chronic pain and fatigue syndromes constitute an increasingly greater societal burden that currently is not being approached effectively by traditional Western medicine. Although the hallmarks of fibromyalgia--chronic widespread pain, fatigue, and multiple other somatic symptoms--have neurophysiologic and endocrinologic underpinnings, these biological aspects derive primarily from psychological variables. Female gender, adverse experiences during childhood, psychological vulnerability to stress, and a stressful, often frightening environment and culture are important antecedents of fibromyalgia. To understand fibromyalgia and related syndromes and to provide optimum care requires a biopsychosocial, not a biomedical, viewpoint.

Just as our caveman forebears were frail in the face of predatory animals, we are frail in today's society of childhood neglect or abuse, bumper-to-bumper traffic, frustration at work, and multiple daily hassles. The same neuroendocrine systems and pain regulatory mechanisms that protected early man during acute stress are still encoded in our genome, but may be maladaptive in psychologically and physiologically vulnerable people faced with chronic stress. Many patients with fibromyalgia become vulnerable because of the long-lasting psychological and neurophysiological effects of negative experiences in childhood. Ill-equipped with positive cognitive, emotional, and behavioral skills as adults, they display maladaptive coping strategies, low self-efficacy, and negative mood when confronted with the inevitable stressors of life. Psychological distress ensues, which reduces thresholds for pain perception and tolerance (already relatively low in women) even further. Converging lines of psychological and neurobiological evidence strongly suggest that chronic stress-related blunting of the HPA, sympathetic, and other axes of the stress response together with associated alterations in pain regulatory mechanisms may finally explain the pain and fatigue of fibromyalgia. Vulnerable people who can be classified by the ACR criteria as having fibromyalgia do not have a discrete disease. They are simply the most ill in a continuum of distress, chronic pain, and painful tender points in the general population.

Protein kinase C (PKC)-dependent activation of the Ras signal transduction cascade is essential for induction of the IL-2 promoter during stimulation of T lymphocytes via the T cell receptor (TCR). In this study, the effects of PKC-activating phorbol myristate acetate (PMA) on Ras-dependent activation of transcription from the ets/AP-1 Ras-responsive promoter element were examined in human T cells. Pretreatment of Jurkat cells with the Src-family PTK inhibitor herbimycin A resulted in a 50% inhibition of transactivation of the reporter following incubation with PMA. Evidence was also obtained to suggest the participation of the leukocyte-specific protein tyrosine phosphatase CD45, a regulator of Src-like PTKs, in the PMA-induced activation of the Ras/Raf pathway. First, PMA-induced transactivation of ets/AP-1 is diminished 75% in CD45-negative variants, compared with CD45-positive cells. Second, engagement of CD45 by monoclonal antibodies suppresses the PMA response from the reporter construct. Taken together, these data suggest that Src-related proteins mediate PKC-dependent activation of the Ras/Raf pathway and implicate CD45 in the TCR-independent activation of T lymphocytes induced by agents such as PMA.

DNA-dependent protein kinase (DNA-PK) consists of a DNA binding subunit (Ku autoantigen), and a catalytic subunit (DNA-PKcs). In the present study, human autoantibodies that recognize novel antigenic determinants of DNA-PK were identified. One type of autoantibody stabilized the interaction of DNA-PKcs with Ku and recognized the DNA-PKcs -Ku complex, but not bio-chemically purified DNA-PKcs. Another type recognized purified DNA-PKcs. Autoantibodies to Ku (p70/p80 heterodimer), 'stabilizing' antibodies, and antibodies to DNA-PKcs comprise a linked autoantibody set, since antibodies recognizing purified DNA-PKcs were strongly associated with stabilizing antibodies, whereas stabilizing antibodies were strongly associated with anti-Ku. This hierarchical pattern of autoantibodies specific for components of DNA-PK (anti-Ku > stabilizing antibodies > anti-DNA-PKcs) may have implications for the pathogenesis of autoimmunity to DNA-PK and other chromatin particles. The data raise the possibility that altered antigen processing and/or stabilization of the DNA-PKcs-Ku complex due to autoantibody binding could play a role in spreading autoimmunity from Ku to the weakly associated antigen DNA-PKcs.

Objective: To determine the specificity of anti-CD45 autoantibodies in systemic lupus erythematosus (SLE) for native CD45 and for CD45 expressed by T cells and B cells, and at different stages of cellular activation., Methods: CD45 purified from different types of lymphocytes was examined by immunoblotting with sera from patients with SLE. Indirect immunofluorescence experiments were performed with purified anti-CD45 autoantibodies., Results: IgM anti-CD45 autoantibodies in SLE recognize native CD45 expressed on the surface membrane of viable lymphocytes and CD45 purified from activated peripheral T cells and certain T cell lines, but not CD45 purified from B cells or resting peripheral T cells. The presence or absence of reactivity is independent of the individual isoforms expressed., Conclusion: Recognition of CD45 by IgM antilymphocyte autoantibodies in SLE varies with the lineage and state of activation of the lymphocyte target. This pattern of reactivity is consistent with autoantibody specificities involving CD45 glycoforms, rather than CD45 isoforms.

SLE is dramatically more prevalent in persons of African descent than in other populations. Several genes in the class III region of the MHC have been considered as potential susceptibility loci for this disorder, but the primary association(s) remains unknown. The stress protein gene, hsp70-2, is of special interest in this regard because it encodes a protein functionally relevant to antigen processing and presentation and has itself been identified as a putative susceptibility locus in organ-specific autoimmune diseases in Caucasians. To clarify the relationship of the hsp70-2 gene to SLE in African Americans, genomic DNA from 46 patients and 42 appropriately matched control subjects was analyzed for an RFLP of the hsp70-2 gene using the probe pH2.3 and the restriction endonuclease PstI, which identifies alleles of 8.5 and 9.0 kb. The 8.5-kb hsp70-2 allele was associated with SLE in this population (X2 = 8.2473, p = 0.0044). This association was not due to linkage disequilibrium with the C4A deletion or with HLA-DR3, as has been reported in Caucasians with IDDM. These data suggest that the 8.5-kb hsp70-2 allele may be an independent susceptibility marker for SLE in African Americans.

"Anticardiolipin" autoantibodies (aCL) bind to anionic phospholipids only in the presence of beta 2-glycoprotein I (beta 2GPI), a phospholipid-binding plasma protein. The exact role of beta 2GPI in the antigenic specificity of these autoantibodies is unclear, however. Experiments were performed to determine whether aCL recognize beta 2GPI in the absence of phospholipid or neo-Ags formed as a consequence of the beta 2GPI-phospholipid interaction. Although aCL+ IgG fractions did not bind to beta 2GPI alone in ELISAs that used standard polystyrene immunoassay plates, significant specific binding was detected when beta 2GPI was coated on gamma-irradiated ("high binding") polystyrene plates. This difference was associated with the greater density of beta 2GPI immobilized on the gamma-irradiated plates. Fab' fragments of patient IgG demonstrated little or no binding to immobilized beta 2GPI in ELISA, indicating a critical role for Ab bivalency. Inhibition studies of three aCL+ IgG fractions confirmed their specificity for beta 2GPI and demonstrated low affinity binding to fluid-phase beta 2GPI (Kd values of approximately 10(-5) M). aCL binding to beta 2GPI was not a result of phospholipid contamination of the assays, as determined by microphosphate assay and by lipid extraction of IgG and beta 2GPI preparations. In summary, these experiments indicate that IgG aCL are intrinsically low affinity Abs to beta 2GPI. Ab binding to beta 2GPI on a microtiter plate or anionic phospholipid membrane is dependent upon the marked increase in avidity provided by engagement of both Ag binding sites of a given IgG molecule. The data support the hypothesis that phospholipid-bound beta 2GPI is the physiologic target of aCL.

Normal individuals possess low levels of autoantibodies specific for certain peptide defined regions of T-cell receptor (Tcr) variable regions, particularly CDR1 and Fr3. These regions are predicted to be exposed on the surface of the native molecule and, by analogy and comparison with immunoglobulins, correspond to public idiotype determinants. The anti-Tcr idiotype antibodies appear to be ubiquitous and we propose that they play a role in the regulation of T-cell function. To delineate the parameters of expression of these antibodies, we characterized anti-Tcr antibody activity in normal individuals, in those suffering from the autoimmune diseases rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and in patients with non-autoimmune arthritis (osteoarthritis) as a disease control. There were significant increases in autoantibody levels in the autoimmune patients. There was also variation in isotype and the particular variable regions recognized. IgM autoantibodies directed against a few peptide defined determinants were elevated in RA, whereas SLE patient sera showed high levels of IgG binding to a broad spectrum of Tcr peptides.

Immunoglobulins and their close relatives, the antigen-specific T-cell receptors, are recognition proteins that express structures which readily serve as self-immunogens. Healthy humans can produce antibodies against variable region-defined recognition structures termed idiotypes, as well as against constant region structures, and the levels of these can increase markedly in autoimmune disease; e.g., rheumatoid factors are autoantibodies directed against a conformational determinant of the gamma heavy chain. More recent analyses employing synthetic peptide technologies and construction of recombinant T-cell receptors document that autoantibodies directed against both variable and constant region markers of the alpha/beta T-cell receptor occur in healthy individuals. Alterations in levels of antibody, usage of IgM or IgG isotypes, and specificity for particular peptide-defined regions vary with natural physiological processes (aging, pregnancy), with artificial allografting, with retroviral infection, and with the inception and progression of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus). Two of the major autoimmunogeneic regions of the Tcr alpha/beta are "constitutive" markers inasmuch as all individuals tested produce antibodies against these regions. The most frequently observed autoantibodies are against Tcr V beta CDR1 and Fr3 markers. It is hypothesized that these are normally involved in immunoregulation. Autoantibodies usually are not detected against CDR2 region determinants, or the "private idiotypes" defined by the CDR3 region, or the highly conserved FR4 segment specified by the joining gene segment. However, autoantibodies against the CDR2 of the Tcr alpha chain occur in some SLE patients, and healthy pregnant women produce antibodies against the common peptide determinant expressed by the joining gene and the beginning of the C alpha or C beta domain. Although the precise role of the naturally occurring autoantibodies in immunoregulation remains to be determined, modification of the course of autoimmune diseases in experimental rodent models (experimental allergic encephalomyelitis) has been successfully carried out by immunization with synthetic peptides corresponding to the CDR2 and Fr3/CDR3 segments, and immunization of humans with synthetic V beta CDR2 segments may prove helpful in multiple sclerosis. Moreover, infusion of intravenous immunoglobulins has been successful in the treatment of many autoimmune diseases, including examples where levels of T cells bearing particular V beta gene subsets were elevated. The recent knowledge gained from T-cell receptor structural analysis and antigenic modeling holds promise for determining the roles of particular variable domain structures in antigen recognition MHC-restriction and immunoregulation, and in the development of synthetic and recombinant reagents for modulation of autoimmune and infectious diseases.

The fetus is a natural allograft that is protected from immunologic rejection by a complex set of structural and regulatory mechanisms. We determined whether healthy pregnant women differed significantly from healthy non-pregnant controls in their capacity to produce autoantibodies to defined antigenic determinants of the alpha/beta T-cell receptor. Although controls and pregnant women expressed comparable levels of autoantibodies against an intact recombinant T-cell receptor containing the complete V alpha/V beta structures, analysis of comparative reactivity against individual peptide segments of the molecules, indicated enhanced reactivity to regions corresponding to the CDR1 of the alpha chain and to the Fr3 of the variable region of the beta chain. A major difference was noted by increased reactivity of IgG autoantibodies of pregnant women to peptides corresponding to the "switch" region joining the variable and constant domains. This was noted with both the Tcr alpha and beta chains and was directed against highly conserved determinants within these molecules. Antibodies to this region are lacking in the non-pregnant controls. It is possible that autoantibodies directed against conserved regions of the T-cell receptor might function in the suppression of T-cell reactivity of fetal determinants.

A 24-year-old black woman developed polymyositis with autoantibodies to threonyl-tRNA synthetase in the 2nd trimester of her 3rd pregnancy. This was complicated by fetal loss and the development of severe relapsing myositis resistant to corticosteroid and azathioprine therapy. These features were also common in other cases in the literature. Antisynthetase antibodies had not been reported in myositis occurring during pregnancy and may be of interest regarding the pathogenesis of inflammatory myopathy complicating pregnancy.

Patients with SLE develop IgM autoantibodies to different isoforms of CD45, the major surface membrane protein tyrosine phosphatase on lymphocytes and other nucleated hemopoietic cells. Because such autoantibodies could have a potential role in the development of immune dysfunction in this disorder, we performed a series of experiments to characterize their antigenic specificity further. Blots of recombinant E. coli fusion proteins encoded by exons 3-7 of the p220 and p180 isoforms were uniformly non-reactive with SLE IgM, suggesting that anti-CD45 autoantibodies in SLE are directed against conformational and/or carbohydrate epitopes, rather than linear polypeptide epitopes. This issue was examined further using chemically and enzymatically modified CD45 purified from T cells by lectin affinity chromatography as substrates. Treatment of CD45 with 25 mM sodium-m-periodate, sufficient to abrogate binding to various lectins, abolished the reactivity with SLE anti-CD45 autoantibodies. On the other hand, digestion of CD45 with neuraminidase enhanced the binding of anti-CD45 autoantibodies from some of the SLE sera. This result probably reflects decreased steric hindrance or charge repulsion because the binding of mouse monoclonal antibodies directed against linear polypeptide epitopes of CD45 was similarly enhanced. Digestion of CD45 with N-glycosidase F had no effect on autoantibody staining. Taken together, these data suggest that IgM anti-CD45 autoantibodies in SLE recognize non-sialylated carbohydrate determinants in the highly O-glycosylated polymorphic domains of CD45.

It has been reported that antiphospholipid autoantibodies do not recognize phospholipid alone, but rather the plasma protein beta 2-glycoprotein I (beta 2GPI), or a beta 2GPI-phospholipid complex. In vitro beta 2GPI binds to anionic phospholipids and inhibits the prothrombinase activity of procoagulant membranes. In light of the fact that lupus anticoagulants, a type of antiphospholipid antibody, have similar anticoagulant properties, the relationship of beta 2GPI to lupus anticoagulant activity was investigated. IgG from patients with autoimmune diseases or syphilis were tested for anticardiolipin reactivity and lupus anticoagulant activity in the presence and absence of beta 2GPI. As expected, anti-cardiolipin reactivity associated with autoimmune disease was beta 2GPI dependent. In contrast, IgG from a patient with syphilis recognized cardiolipin alone and binding was inhibited by beta 2GPI. Autoimmune antiphospholipid antibodies prolonged the dilute Russell viper venom time of normal plasma, but had no effect on beta 2GPI-depleted plasma. Antiphospholipid antibodies associated with syphilis had no anticoagulant effect. RP-1, an anti-beta 2GPI mAb, had anticoagulant effects similar to those of autoimmune antiphospholipid antibodies. These data demonstrate that antiphospholipid autoantibodies exert lupus anticoagulant activity via an interaction with beta 2GPI. These antibodies and RP-1 appear to amplify the anticoagulant effect of beta 2GPI itself.

IgM autoantibodies to nucleolin and histone H1 are strongly associated in the serum of patients with systemic lupus erythematosus. IgM eluted from immobilized nucleolin specifically stained histone H1 blotted to nitrocellulose; conversely, IgM eluates prepared from immobilized histone H1 stained nucleolin blots. We conclude that the linkage of anti-nucleolin and anti-histone H1 autoantibodies in SLE is due, at least in part, to immunologic cross-reactivity between these two autoantigens, which share certain similar structural features.

Autoantibodies to surface antigens on lymphocytes and other cells of the immune system may contribute to the development of immunoregulatory and other cellular immune abnormalities in patients with active systemic lupus erythematosus. Of special interest in this respect are autoantibodies to CD45 (leukocyte-common antigen, T200), a plasma membrane protein tyrosine phosphatase implicated in the regulation of lymphocyte functional activity, including cytotoxicity, proliferation, and differentiation.

Unselected sera from patients with various rheumatic, inflammatory bowel, and autoimmune skin diseases (n = 268) were examined against human cell lysate by immunoblotting procedures, to determine the prevalence of autoantibodies to stress proteins (heat-shock proteins) hsp60 (homolog of Escherichia coli groEL and mycobacterial 65K antigens), hsp73, and hsp90. Using standard, sensitive and specific assay conditions, IgG and IgM autoantibodies to these stress proteins were not demonstrable, or were detected infrequently, in sera from control subjects (n = 36) and from patients with rheumatoid arthritis, Sjögren's syndrome, ankylosing spondylitis, Reiter's syndrome, systemic lupus erythematosus, and systemic sclerosis. Autoantibodies to hsp60 were relatively more common (greater than or equal to 20% of sera) in patients with mixed connective tissue disease, polymyositis/dermatomyositis, psoriatic arthritis, inflammatory bowel disease, epidermolysis bullosa acquisita, and bullous pemphigoid. Anti-hsp73 autoantibodies were detected in 20% or more of the sera from patients with Lyme disease and ulcerative colitis. Taken together, these data extend the spectrum of autoimmune and inflammatory diseases in which humoral anti-stress protein autoreactivity develops. However, the paucity of humoral autoreactivity to stress proteins in patients with systemic lupus erythematosus and rheumatoid arthritis argues against a direct role of anti-stress protein autoantibodies in the pathogenesis of these disorders.

The University of North Carolina Arthritis Center combines the broadly-based research agenda of the Thurston Arthritis Research Center with comprehensive interdisciplinary clinical programs in rheumatology, orthopaedics, and pediatric rheumatology. In keeping with the University's long tradition of service to the people of North Carolina, a primary aim of the Center is to provide the citizens of this state with the best available arthritis care and prevention strategies. The approach here is twofold. New knowledge is created by laboratory investigation of basic disease mechanisms, by clinical studies of new therapies, by social and behavioral research to better understand how patients and their families cope and adjust to chronic arthritis, and by health services research that examines arthritis from a societal perspective. This information, together with advances in rheumatology and related fields from Duke and other institutions, is then applied to optimum clinical and educational services for North Carolina patients and their physicians.

The 110-kDa intracellular phosphoprotein (110K) described previously by this laboratory as a common IgM autoantigen in SLE and certain other systemic autoimmune disorders and viral infections is identified as nucleolin in the present investigation. Using rabbit antiserum to rat nucleolin as a probe, IgM autoantibody-reactive 110K co-migrated with human lymphocyte nucleolin in one- and two-dimensional immunoblots. Rabbit anti-nucleolin also specifically depleted autoreactive 110K from detergent lysates of human cells. Because nucleolin shares amino acid sequence similarity and/or forms dynamic particles with other prominent autoantigens, the present observation raises the possibility that the nucleolin/anti-nucleolin system may be of special significance for the development of humoral autoreactivity to nuclear Ag.

Autoantibodies in the sera of patients with systemic lupus erythematosus were examined with respect to their specificity for proteolytic fragments of histone H1 that retain, or do not retain, DNA-binding domains. 16 of 31 sera contained IgG and IgM antibodies to histone H1. IgM antibodies to H1 in 8 sera (50%) were directed at 18 kD and 20 kD alpha-chymotrypic H1 fragments that bore binding sites for DNA, as identified by staining immunoblots containing the fragments with ssDNA plus 6/0, a mouse monoclonal antibody against ssDNA, IgM with this type of histone H1 specificity did not react with comparably-sized V8 protease fragments of H1. IgM antibodies to H1 in the other patients were directed against entirely different epitopes which were preserved in V8 protease digests of H1. In serial studies of three patients during different phase of their SLE, the level of antibodies against the 18 kD and 20 kD histone H1 fragments varied in parallel with the level of anti-ssDNA antibodies in one and varied inversely in the other two. The data suggest that a significant proportion of autoantibodies to histone H1 are directed at a limited number of epitopes localized to H1 fragments containing DNA-binding sites.

At birth, the immune system is biased toward recognition of microbial antigens in order to protect the host from infection. Recent data suggest that an important initial line of defense in this regard involves autologous stress proteins, especially conserved peptides of hsp60, which are presented to T cells bearing gamma delta receptors by relatively nonpolymorphic class lb molecules. Natural antibodies may represent a parallel B cell mechanism. Through an evolving process of "physiological" autoreactivity and selection by immunodominant stress proteins common to all prokaryotes, B and T cell repertoires expand during life to meet the continuing challenge of infection. Because stress proteins of bacteria are homologous with stress proteins of the host, there exists in genetically susceptible individuals a constant risk of autoimmune disease due to failure of mechanisms for self-nonself discrimination. That stress proteins actually play a role in autoimmune processes is supported by a growing body of evidence which, collectively, suggests that autoreactivity in chronic inflammatory arthritis involves, at least initially, gamma delta cells which recognize epitopes of the stress protein hsp60. Alternate mechanisms for T cell stimulation by stress proteins undoubtedly also exist, e.g., molecular mimicry of the DR beta third hypervariable region susceptibility locus for rheumatoid arthritis by a DnaJ stress protein epitope in gram-negative bacteria. While there still is confusion with respect to the most relevant stress protein epitopes, a central role for stress proteins in the etiology of arthritis appears likely. Furthermore, insight derived from the work thus far in adjuvant-induced arthritis already is stimulating analyses of related phenomena in autoimmune diseases other than those involving joints. Only limited data are available in the area of humoral autoimmunity to stress proteins. Autoantibodies to a number of stress proteins have been identified in SLE and rheumatoid arthritis, but their pathogenetic significance remains to be established. Nevertheless, the capacity of certain stress proteins to bind to multiple proteins in the nucleus and cytoplasm both physiologically and during stress or injury to cells, suggests that stress proteins may be important elements in the "immunogenic particle" concept of the origin of antinuclear and other autoantibodies. In short, this fascinating group of proteins, so mysterious only a few years ago, has impelled truly extraordinary new lines of investigation into the nature of autoimmunity and autoimmune disease.

Rabbit antibodies to hsp58 (P1), the human homologue of the Escherichia coli stress protein groEL, react specifically in indirect immunofluorescence and complement-dependent microcytoxicity experiments with a cell surface antigen expressed constitutively by T cell lines bearing gamma/delta receptors. This anti-hsp58-reactive antigen is not demonstrable on T cells that express alpha/beta receptors or on various cells that lack T cell receptors. Certain evidence was obtained to suggest that the target antigen on the surface of gamma/delta T cells is a approximately 77-kD protein distinct from intracellular hsp58 and known members of the hsp70 stress protein family. While the exact nature and significance of this anti-hsp58-reactive protein remain to be determined, these data may help to clarify the roles of groEL-related stress proteins and gamma/delta cells that recognize groEL homologous in immunologic defense against infection and in autoimmune disease.

Nearly one-third of IgM antilymphocyte autoantibody-positive sera from patients with systemic lupus erythematosus (SLE) contain IgM antibodies to one or more 180-220-kD molecules (p180, p190, p205, and p220) in blots of glycoproteins purified from T cells by wheat germ agglutinin affinity chromatography. Identity of these IgM targets with multiple isoforms of CD45 was established by their specific depletion from T cell glycoproteins by immunoprecipitation with T191, a monoclonal antibody (mAb) that reacts with an epitope common to all CD45 isoforms. Although the anti-CD45 autoantibodies recognize higher molecular weight isoforms primarily, antigenic specificity in this system is quite heterogeneous and includes multiple distinct CD45 isoforms on different types of T cells that are, at least in part, different from those reactive with mAbs 2H4 and UCHL-1. Because CD45 is a major membrane protein tyrosine phosphatase that plays a critical role in antigen-induced T cell activation, the present data may be relevant to some of the antilymphocyte antibody-mediated immunologic abnormalities that characterize SLE and related autoimmune diseases.

Sera from patients with systemic lupus erythematosus frequently contain IgM antibodies to glycoproteins of Mr 46,000 and approximately 200,000 isolated from nonionic detergent lysates of mature T cells by affinity chromatography with solid-phase wheat germ agglutinin. Autoantibodies of this specificity correlate strongly with the presence of IgM anti-T cell autoantibodies, as determined by independent indirect immunofluorescence and complement-dependent microcytotoxicity assays, and are specifically absorbed by incubation of patient serum with viable T cells. Collectively, the data suggest that gp46 and, to a lesser extent, gp approximately 200 represent major targets of IgM antilymphocyte autoantibodies in systemic lupus erythematosus.

Because nonspecialized physicians provide care for the vast majority of patients with rheumatic disorders, we surveyed 327 internal medicine and family medicine residents with respect to the nature of their training in rheumatology. Although most internal medicine residents had access to rheumatologists for training and had taken formal rheumatology rotations, this was often not the case for family medicine residents. Deficiencies evident in both types of programs included limited access to rheumatology electives; insufficient exposure to certain major categories of rheumatic disease, e.g., the spondyloarthropathies and systemic autoimmune disorders; and lack of direct participatory experience in orthopedics, rehabilitation, and psychosocial aspects of rheumatology.

Utilizing nonionic detergent lysates of human lymphoid and non-lymphoid cells as substrate, IgM and/or IgG antibodies to a 110-kDa/isoelectric point 5.4 phosphoprotein (110K) was demonstrated in serum from patients with SLE or certain other systemic autoimmune disorders by immunoblotting and immunoprecipitation. Ig of this specificity was not demonstrable in serum from normal individuals, but, in a limited survey, was detected in serum from patients with acute hepatitis A or infectious mononucleosis. 110K shares a number of properties with nucleolin, i.e., identical Mr and isoelectric point, localization in both the nucleus and the cytosol, increased expression in rapidly dividing cells, and shown to be distinct from already defined autoantigens of similar size, i.e., topoisomerase I, PM-Scl, and RNA polymerase I. Because 110K could bind denatured DNA, as demonstrated by its specific absorption by DNA-cellulose and by its reactivity with monoclonal anti-ssDNA antibody in the presence of denatured DNA, special efforts were made to distinguish reactivity of pre-formed DNA/anti-DNA complexes in SLE serum from that due to specific anti-110K autoantibodies. Although binding to 110K could be mediated by DNA and anti-DNA in some SLE sera, the accumulated evidence supports the existence of a major new autoantibody system in SLE, other autoimmune diseases, and certain virus infections.

Sera from 20 patients with systemic lupus erythematosus (SLE) and active central nervous system (CNS) dysfunction were examined by indirect immunofluorescence for antibodies to neuronal membrane determinants. Warm-reactive IgG antibodies were demonstrable in 82% (9/11) of patients with clinical evidence for seizures or diffuse CNS disease, but these antibodies generally were absent in non-CNS SLE sera or when focal neurologic deficit or psychosis was the primary CNS manifestation. Cold-reactive antibodies of the IgM class were equally prevalent in patients with or without CNS disease and appeared to be more directly correlated with extra-CNS systemic illness. Absorption experiments with lymphocytes, brain homogenate, and various other tissues suggested a predominant brain-specificity for IgG antibodies and partial lymphocyte cross-reactivity for IgM antibodies. Interpretations of this special association between IgG anti-brain antibodies and diffuse CNS dysfunction in SLE are discussed.

Although surface membrane density of complement receptor type one (CR1) on erythrocytes (E) is probably an inherited trait among normal individuals, recent evidence from our laboratories suggests that the reduced number of CR1 per E observed in patients with systemic lupus erythematosus (SLE) results from acquired as well as genetic factors. In the present investigation, the number of CR1 per E was quantitated with 125I-monoclonal anti-CR1 and was found to vary inversely with disease activity in patients with SLE who were followed serially for as long as 14 mo. Although evidence for E surface-bound immune complexes or fixed C3b/iC3b was not obtained, periods of disease activity and low amounts of CR1 per E correlated with the presence of 100 to 800 molecules per E of fixed C3dg fragments (less than 100 C3dg per E in normal subjects). Reduced CR1 and excess fixed C3dg on E also were observed in patients with other disorders associated with complement activation, including chronic cold agglutinin disease, autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria (PNH), Sjögren's syndrome, and mycoplasma pneumonia. A significant negative correlation (r = -0.498) between CR1/E and fixed C3dg/E was demonstrable in 255 individual assays evaluated by regression analysis. CR1 decreased and fixed C3dg increased during active disease; the converse was obtained during remission. In patients with active SLE, both serum complement activity and E CR1 decreased, whereas fixed C3dg fragments increased. By piecewise linear regression analysis, the appearance of 100 to 400 C3dg molecules on patients' E corresponded to a 27 to 60%, reduction in the number of CR1 per E (p less than 0.0002), confirming that fixation of C3 to E was correlated with a loss of CR1. In patients with PNH, low values for CR1 were observed on moderately complement-sensitive PNH type II E in association with increased fixed C3 fragments; however, the markedly complement-sensitive PNH type III E had essentially normal amounts of CR1 and bore little fixed C3. The addition of soluble DNA/anti-DNA immune complexes to normal blood generated levels of fixed C3dg fragments on E comparable to those observed on E from patients with SLE. Kinetic experiments indicated that C3b was fixed to E during the process of immune complex binding and release from E CR1, and that this fixed C3b was subsequently degraded rapidly to fixed iC3b and more slowly to fixed C3dg without the loss of CR1 that occurs in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)